Classifications

• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/20—Pills, tablets, discs, rods
  • A61K9/2004—Excipients; Inactive ingredients
  • A61K9/2022—Organic macromolecular compounds
  • A61K9/205—Polysaccharides, e.g. alginate, gums; Cyclodextrin
  • A61K9/2054—Cellulose; Cellulose derivatives, e.g. hydroxypropyl methylcellulose
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/20—Pills, tablets, discs, rods
  • A61K9/2004—Excipients; Inactive ingredients
  • A61K9/2022—Organic macromolecular compounds
  • A61K9/2027—Organic macromolecular compounds obtained by reactions only involving carbon-to-carbon unsaturated bonds, e.g. polyvinyl pyrrolidone, poly(meth)acrylates
• • A—HUMAN NECESSITIES
  • A61—MEDICAL OR VETERINARY SCIENCE; HYGIENE
  • A61K—PREPARATIONS FOR MEDICAL, DENTAL OR TOILETRY PURPOSES
  • A61K9/00—Medicinal preparations characterised by special physical form
  • A61K9/20—Pills, tablets, discs, rods
  • A61K9/2095—Tabletting processes

Definitions

• the invention relates to a special method for producing stable, solid pharmaceutical preparations with high bioavailability and controlled release containing poorly soluble active ingredients and polymeric auxiliaries and the preparations thus produced.
• Solid solutions or coprecipitates from active substances such as Dihydropyridines and polyvinyl lactams are known.
• the production can e.g. by dissolving the active ingredient and auxiliary in organic solvents and further processing into tablets or by shaping an active ingredient-auxiliary melt, e.g. by injection molding or extrusion and subsequent calendering.
• Suitable organic solvents such as chlorinated hydrocarbons, ketones or alcohols represent an environmental burden and must therefore be recovered with great technical effort during or after the production of solid solutions.
• solvents that form explosive or ignitable mixtures with air the entire process must be explosion-proof.
• Large amounts of excipients are required because the organic solution of active ingredient and polymer has to be applied to a carrier, for example a cross-linked polymer, for further drug formation (cf. EP 0 232 155).
• the complete removal of the solvent used from the product is usually complex or impossible, so that an undesirable content of residual solvents remains in the product. Coprecipitates produced in this way often tend to recrystallize the active ingredient and are therefore not stable in storage or show no constant bioavailability over a storage period of several months.
• the active ingredient is mixed with the melt in single- and twin-screw extruders and the subsequent shaping of the extrudate on calender rolls, there are procedural limits to the achievable shape of the particles.
• the cylindrical tablet shape known to the patient with a lateral web cannot be produced or can only be produced to a very limited extent. This results in a reduced acceptance of the medication and runs the risk that the particles obtained with a round or pillow-shaped cross section are confused with candy.
• the present invention was based on the object of overcoming the procedural restrictions mentioned above.
• the problems are solved by the new process, which relates to the production of pharmaceutical preparations by granulation or tableting of powders or granules by conventional methods, followed by thermal dissolution or amorphization of the active ingredient.
• the shaping of the first process step by pressing (tableting) or granulating permits a considerably more advantageous selection of the polymers.
• the molded pharmaceutical preparation is then heated in a subsequent, easy-to-carry out process step.
• the invention thus relates to the production of solid pharmaceutical preparations containing 1 part by weight of one or more poorly soluble active ingredients (I), 0.5 to 50 parts by weight, preferably up to 20 parts by weight, of a cellulose ether (II) and 0 , 5th up to 50 parts by weight, preferably up to 20 parts by weight, polyvinyl lactams or polyvinyl lactam copolymers (III) and, if appropriate, other customary auxiliaries, characterized in that the constituents (I), (II) and (III) in the absence of Mixes solvents and forms them into the desired medicinal preparations and then thermally activates them for at least 30 minutes at temperatures between 50 to 200 ° C, preferably at 80 to 170 ° C.
• Tablets, pellets and granules, in particular tablets, may be mentioned as preferred solid pharmaceutical preparations.
• the duration of the thermal treatment is at least 30 minutes and, depending on the temperature selected, can be up to 3 days, preferably up to 48 hours.
• the cellulose ethers (II) used according to the invention are preferably compounds based on linear alkoxylated cellulose compounds which are used in amounts between 5 and 60% by weight, preferably between 20 and 45% by weight, based on the weight of the ready-to-use preparation.
• Particularly preferred cellulose ethers are compounds with methoxy and hydroxypropyl substituents which, in 2% strength aqueous solutions, have a viscosity of 15 to 100,000 mPa ⁇ s, preferably 50 to 30,000 mPa ⁇ s, for example the products known under the trade names METOLOSE 60 SH, METOLOSE 65 SH and METOLOSE 90 SH.
• the polyvinyllactams (III) used according to the invention are preferably high molecular weight compounds based on polyvinylpyrrolidone or vinylpyrrolidone-vinyl acetate copolymer which have an average molecular weight (weight average M ⁇ w) from 20,000 to 2,000,000, preferably 25,000 to 1,500,000 M ⁇ w and which are used in amounts between 5 and 60% by weight, preferably between 20 and 40% by weight, based on the final weight of the pharmaceutical preparation.
• Linear polyvinylpyrrolidones with a high molecular weight are particularly preferred, for example those known under the trade names KOLLIDON K25, KOLLIDON 90 and KOLLIDON VA 64.
• thermally stable active ingredients can be incorporated into the preparations produced according to the invention. Poorly soluble active ingredients, in particular those from the group of the dihydropyridines, may preferably be mentioned. Proportionally these active ingredients are preferably used in amounts of 5 to 50% by weight, preferably 20 to 35% by weight, of the finished preparation.
• the first step in the present invention is to prepare a solid solution from a preformed system of a powder compact or granules without further mechanical action by thermal treatment.
• This method has the advantage that relatively simple and hitherto conventional manufacturing devices such as tableting machines or drying devices can be used. Furthermore, the method allows the selection of the most effective polymers possible, regardless of the need to shape the melt.
• the preparations according to the invention also have pharmacological advantages due to the absence of undesirable solvent residues and small amounts of excipients.
• coprecipitates prepared with solvents that they can be stored for long periods, particularly under unfavorable conditions such as e.g. high air humidity or elevated temperature (tropics) show recrystallization of the poorly soluble active ingredients after a short time, which leads to a reduction in bioavailability.
• the solvent-free preparations which are thermally activated according to the invention have a significantly higher storage stability and good bioavailability which remains constant over several months.
• the process according to the invention is particularly preferably useful in the preparation of preparations with controlled release of active substance, in particular for sustained-release preparations which are intended to release the active substance linearly over several hours.
• All of the example formulations shown show an almost complete uniform (linear) release of active substance over 6 hours.
• the polyvinyl lactams used provide effective solution mediation and, together with the hydroxypropyl cellulose used, delay the release of the active ingredient over several hours.
• Example 4 The formulation from Example 4 was tableted under identical conditions, but without subsequently carrying out the thermal amorphization. The active ingredient was released under identical conditions as described in the preceding.
• Table 2 Comparative example 1 Drug (I) Nimodipine 45 mg (33.3%) Polymer (III) PVP K 90 53.81 mg (39.8%) Polymer (II) HPMC 60 SH 50 35.96 mg (26.6%) Mg stearate 0.41 mg (0.3%) Table weight 135.18 mg Tablet format 8 r 12 release 60 min. 5% 120 min. 12% 180 min. 18% 240 min. 21% 300 min. 25% 360 min. 25%
• the tablet releases the active substance contained only incompletely.
• An active ingredient-containing tablet was produced by a solvent process.
• an acetone solution of nimodipine in PVP K 25 was applied to Crospovidone M and then tableted with Metolose® 60 SH 50 and milk sugar. No thermal amorphization was carried out.
• the active ingredient was released under identical conditions as described in the preceding.
• Table 3 Comparative example 2nd Drug (I) Nimodipine 45 mg (11.75%) Polymer (III) PVP K 25 112.5 mg (29.37%) Crospovidone M 45 mg (11.75%) Polymer (II) Metolose® 60 SH 50 160 mg (41.78%) Milk sugar 19.5 mg (5.09%) Mg stearate 1 mg (0.26%) Tablet weight 383 mg Tablet format 11 r 18 release 60 min. 17% 120 min. 43% 180 min. 68% 240 min. 90% 300 min. 102% 360 min. 101%
• the tablet releases the active ingredient completely.
• the production process has to be carried out in a vacuum fluidized bed, with extensive protection against explosion, during the acetone granulation.
• the tablet is almost three times as heavy and significantly larger than the tablets of Examples 1 to 4 produced by the process according to the invention.
• An active ingredient-containing tablet was produced by an extrusion process.
• a mixture of nimodipine, PVP K 25 and Crospovidone M was extruded through a counter-swirl twin screw machine at 156 ° C and then tableted with Metolose® 60 SH 50 and milk sugar. No thermal treatment of the tablets was carried out. The active ingredient was released under identical conditions as described in the preceding.
• the tablet releases the active ingredient almost completely. In order to achieve the release profile, about 3.8 times more polymer mass is required than in Example 4.
• the manufacturing process is complex in terms of equipment.
• the substances specified in Table 5 under Examples 5 and 6 were mixed and tablets of the specified format and weight were produced using a conventional tablet press. The thermal activation took place at 170 ° C. for 2 hours. The active substance release was determined in a common release apparatus by the stirring blade method. For this purpose, the tablets were incubated in buffer pH 6.8 at 37 ° C. and 100 rpm. The tablets released the active ingredient according to Table 5 within 8 hours.

Landscapes

• Health & Medical Sciences (AREA)
• Chemical & Material Sciences (AREA)
• Medicinal Chemistry (AREA)
• Pharmacology & Pharmacy (AREA)
• Epidemiology (AREA)
• Life Sciences & Earth Sciences (AREA)
• Animal Behavior & Ethology (AREA)
• General Health & Medical Sciences (AREA)
• Public Health (AREA)
• Veterinary Medicine (AREA)
• Medicinal Preparation (AREA)
• Pharmaceuticals Containing Other Organic And Inorganic Compounds (AREA)

Applications Claiming Priority (2)

Publications (2)

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• 1995
  • 1995-08-29 DE DE19531684A patent/DE19531684A1/de not_active Withdrawn
• 1996
  • 1996-08-16 EP EP96113158A patent/EP0761210A3/fr not_active Withdrawn
  • 1996-08-22 US US08/701,410 patent/US5707655A/en not_active Expired - Fee Related
  • 1996-08-22 JP JP8238639A patent/JPH09110725A/ja active Pending
  • 1996-08-26 CA CA002184145A patent/CA2184145A1/fr not_active Abandoned

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